The membrane protein β-site APP cleaving enzyme 1 (BACE1) is responsible for the β cleavage of the amyloid precursor protein (APP). The cleavage, which has been linked to the pathogenesis of Alzheimer's disease (AD), results in the generation of a small APP fragment (commonly referred to as C99) acting as the immediate substrate for γ secretase (Puglielli, 2008). The sequential β/γ processing of APP results into two small fragments, the amyloid β-peptide (Aβ) and the APP intracellular domain (AICD). Both have neurotoxic properties and both have been linked to the pathogenesis of AD (Cleary et al., 2005; Ghosal et al., 2009; Giliberto et al., 2008; Haass and Steiner, 2001; Klein et al., 2001; Lambert et al., 1998; Lansbury, 1999; Puzzo et al., 2008). BACE1 acts as the rate-limiting enzyme for these processing steps. As a result, genetic disruption of BACE1 in the mouse abolishes both β and γ cleavage of APP and prevents AD neuropathology (Cai, 2001; Luo, 2001). Therefore, mechanisms that regulate levels and activity of BACE1 could be effective targets for the development of therapeutic agents.
We recently reported that nascent BACE1 is transiently acetylated on seven lysine residues in the lumen of the ER (Costantini, 2007) by two ER-based acetyl-CoA:lysine acetyltransferases which we named ATase1 (also known as camello-like 2 and N-acetyltransferase 8B) and ATase2 (also known as camello-like 1 and N-acetyltransferase 8) (Ko and Puglielli, 2009). The Nε-lysine acetylation regulates the ability of nascent BACE1 to complete maturation. In fact, the acetylated intermediates of the nascent protein are able to reach the Golgi apparatus and complete maturation while the non-acetylated intermediates are retained and degraded in the ER Golgi intermediate compartment (ERGIC) (Costantini, 2007; Jonas, 2008). Ex vivo studies show that the levels of BACE1 are tightly regulated by the ATases. In fact, up-regulation of ATase1 and ATase2 increases the levels of BACE1 and the generation of Aβ while siRNA-mediated down-regulation of either transferase achieves the opposite effects (Ko and Puglielli, 2009).